His first foray into the world of entertainment was at the 1893 Chicago World's Columbian Exposition, where he managed the famous strongman, Eugen Sandow.

His stage spectaculars, beginning with his Follies of 1907, were produced annually until 1931. These extravaganzas featured a bevy of beauties chosen personally by "Flo" Ziegfeld, prominent composers such as Irving Berlin, George Gershwin, and Jerome Kern, and elaborate costumes and sets.

His promotion of the Polish-born Anna Held as a Parisian beauty, including press releases about her milk baths, brought her fame and set a pattern of star making through publicity. Ziegfeld never married Anna, but they maintained a common-law relationship, outrageously scandalous in that day; it ended in 1913, allegedly because he moved his mistress into the apartment above theirs. In the highly-fictionalized The Great Ziegfeld, Florenz (William Powell) and Anna (Luise Rainer in an Academy Award-winning performance) are married, and Anna is a French native.

The Follies launched the careers of Fanny Brice, W. C. Fields, and Eddie Cantor. Ziegfeld married Billie Burke in 1914, and they had a daughter, Patricia.

Ziegfeld produced other landmarks as well, including Show Boat. Although he recognized its artistic value, he was terrified Show Boat would fail because of its unusually dramatic storyline. According to an eyewitness, the audience barely applauded on opening night, but it was not because they disliked the show, but because they were so taken aback. It was a great success, and in 1932, after Ziegfeld lost much of his money in the stock market crash, he staged a revival of Show Boat. It became the biggest grosser on Broadway, until the Great Depression affected its run. Later that same year, Ziegfeld died from a lung infection related to pleurisy .

Ziegfeld is interred in Kensico Cemetery in Valhalla, Westchester Co., New York.